The immediate early protein 1 of the human herpesvirus 6B counteracts NBS1 and prevents homologous recombination repair pathways

Integration of viral DNA in the genome of host cells triggers host-pathogens interaction that are consequential for the virus and the infected cells. In cells semi-permissive for viral replication, the human herpesvirus 6B (HHV-6B) integrates its genome into the host telomeric sequences. Interestingly, HHV-6B integration in gametes leads to a condition called inherited chromosomally integrated HHV-6B (iciHHV-6B), where the newborn carries a copy of HHV-6B in every cell of its body and is associated with health issues such as spontaneous abortion rates, pre-eclampsia and angina pectoris when transmitted to its offspring. Unlike retroviruses, the mechanism that leads to viral integration of DNA viruses and the consequences of these events on host cells are not well characterized. Here, we report that HHV-6B infection induce genomic instability by suppressing the ability of the host cell to sense DNA double-strand break (DSB). We discovered that this phenotype is mediated by the ability of the immediate-early HHV-6B protein IE1 to bind, delocalize, and inhibit the functions of the DNA damage sensor NBS1. These results raise the possibility that the genomic instability induced by the expression of IE1 from integrated genomes contributes to the development of iciHHV-6B-associated disease. As reported for other types of viruses, the inhibition of DSB sensing and signaling promotes viral replication. However, HHV-6B integration is not affected when this pathway is inhibited, supporting models where integration of the viral genome at telomeric sequence is dictated by mechanisms that promote telomere-elongation in a given infected cell and not solely DNA repair mechanisms. ### Competing Interest Statement The authors have declared no competing interest.